A novel FBW7/NFAT1 axis regulates cancer immunity in sunitinib-resistant renal cancer by inducing PD-L1 expression

Background: Tyrosine kinase inhibitors (TKIs) alone and in combination with Immune Checkpoint inhibitors (ICIs) have been shown to be beneficial for the survival of metastatic renal cell carcinoma (mRCC) patients, but resistance to targeted therapy and ICIs is common in the clinic. Understanding the underlying mechanism is critical for further prolonging the survival of renal Cancer patients. Nuclear factor of activated T cell 1 (NFAT1) is expressed in immune and nonimmune cells, and the dysregulation of NFAT1 contributes to the progression of various type of malignant tumors. However, the specific role of NFAT1 in RCC is elusive. As a regulator of the immune response, we would like to systemically study the role of NFAT1 in RCC.

Methods: TCGA-KIRC dataset analysis, Western blot analysis and RT-qPCR analysis was used to determine the clinic-pathological characteristic of NFAT1 in RCC. CCK-8 assays, colony formation assays and xenograft assays were performed to examine the biological role of NFAT1 in renal Cancer cells. RNA-seq analysis was used to examine the pathways changed after NFAT1 silencing. ChIP-qPCR, coimmunoprecipitation analysis, Western blot analysis and RT-qPCR analysis were applied to explore the mechanism by NAFT1 was regulated in the renal Cancer cells.

Results: In our study, we found that NFAT1 was abnormally overexpressed in RCC and that NFAT1 overexpression was associated with an unfavorable prognosis. Then, we showed that NFAT1 enhanced tumor growth and regulated the immune response by increasing PD-L1 expression in RCC. In addition, we demonstrated that NFAT1 was stabilized in sunitinib-resistant RCC via hyperactivation of the PI3K/Akt/GSK-3β signaling pathway. Furthermore, our study indicated that downregulation of the expression of FBW7, which promotes NFAT1 degradation, was induced by FOXA1 and SETD2 in sunitinib-resistant RCC. Finally, FBW7 was found to contribute to modulating the immune response in RCC.

Conclusions: Our data reveal a novel role for the FBW7/NFAT1 axis in the RCC response to TKIs and ICIs. NFAT1 and its associated signaling pathway might be therapeutic targets for RCC treatment, especially when combined with ICIs and/or TKIs.